3-pyridyl-9h-dibenzo(c,f)-s-triazolo(4,3-a)azepine

ABSTRACT

1. 3-(2-PYRIDYL)-9H-DIBENZO(C,F)-S-TRIAZOLO(4,3-A) AZEPINE.

United States Patent 3,850,942 3-PYRIDYL-9H-DIBENZO[c,f]-s-TRIAZOLOl4.3-a]AZEPINE Jackson B. Hester, Jr., Galesburg, and JacobSzmuszkovicz, Kalamazoo, Mich., assignors to The Upjohn Company,Kalamazoo, Mich.

No Drawing. Continuation-impart of abandoned application Ser. No.227,916, Feb. 22, 1972. This application Dec. 8, 1972, Ser. No. 313,208

Int. Cl. C07d 31/42 US. Cl. 260--296 P 3 Claims 10 ABSTRACT OF THEDISCLOSURE Compounds of the formula III:

inwhich R and R are each selected from the group consisting of hydrogenand alkyl of 1 to 3 carbon atoms, inclusive, and N-R in which R isselected from the group consisting of hydrogen, alkyl defined as above,

v in which n is 1 to 4, inclusive, and R is hydrogen or alkyl defined asabove, or R is in which R, and R are each selected from the groupconsisting of hydrogen and alkyl as defined above or together ispyrrolidino, or piperidino wherein R is selected from the groupconsisting of hydrogen, alkyl, hydroxymethyl defined as above,

3,850,942 Patented Nov. 26, I974 in which n is 0 to 4, inclusive, and Ris hydrogen or alkyl defined as above or R is in which n is defined asabove, and R and R are each selected from the group consisting ofhydrogen and alkyl as defined above, or

together is pyrrolidino, or piperidino; wherein R and R are selectedfrom the group consisting of hydrogen, fluoro, chloro, bromo, iodo,amino, nitro, cyano, alkyl, defined as above, triflnoromethyl, andalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, and alkanoylamino, inwhich the carbon moiety is of 1 to 3 carbon atoms, inclusive, anddialkylamino in which alkyl is defined as above, are prepared byreacting a thio compound of formula I R, 1 R4 I wherein X is oxygen,sulfur,

s Ra in which R and R are defined as above, and NH; wherein R and R aredefined as above, with a selected carboxylic acid hydrazide or, in twosteps, with hydrazine and then a carboxylic acid halide or anhydride.The resulting products II can be further modified to yield the othercompounds corresponding to formula II, as defined above.

Compounds of formula III and the pharmacologically acceptable acidaddition salts and N-oxides thereof have central nervous antidepressantactivity and can be used in mammals and birds.

cRoss REFERENCE TO RELATED APPLICATION This application is acontinuation-in-part of applicalication Ser. No. 227,916 filed Feb. 22,1972, now abandoned.

BACKGROUND OF THE INVENTION Field of the invention This invention isdirected to new organic compounds and is particularly concerned withnovel compounds of formulae II and HI and process-es for the productionthereof.

- The novel compounds and the process of production therefor can beillustratively represented as follows:

R, g g R! I {xii Q Ra a N/ B4 In I? N/ Br wherein X is selected from thegroup consisting of oxygen, sulfur,

in which R and R are each selected from the group consisting of hydrogenand alkyl of 1 to 3 carbon atoms, inclusive, and N-R in which R isselected from the group consisting of hydrogen, alkyl defined as above,

in which n is 1 to 4, inclusive, and R is hydrogen alkyl defined asabove, or R is and in which R, and R are each selected from the groupconsisting of hydrogen and alkyl as defined above or in which R and Rare defined as above and NH; wherein R is selected from the groupconsisting of hydrogen, hydroxymethyl, alkyl defined as above,

in which n is 0 to 4, inclusive, and R is hydrogen and alkyl defined asabove, or R is /R1 -C,,'H2 N or ---CECO H R5 R3 in which n' is definedas above, and R7 and R are each selected from the group consisting ofhydrogen and alkyl as defined above, or

together is pyrrolidino, or piperidino, wherein R and R are selectedfrom the group consisting of hydrogen, fluoro, chloro, bromo, iodo,amino, nitro, cyano, alkyl defined as above, trifluoromethyl, andalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, and alkanoylamino, inwhich the carbon moiety is of l to 3 carbon atoms, inclusive, anddialkylamino in which alkyl is defined as above.

If R of compound II hydrogen, other R substituents are obtained by e.g.halogenation and then reacting the halo compounds with ammonia,substituted amines, cyanides and the like by conventional procedures.Additional methods can be employed to obtain other compounds embraced bythis invention and corresponding to formula III ' wherein X is selectedfrom the group consisting of oxygen, sulfur,

in which R and R are each selected from the group consisting of hydrogenand alkyl of 1 to 3 carbon atoms, inclussive; and N-R in which R isselected from the group consisting of hydrogen, alkyl defined as above,

HsC-N' N 0,,H2,,-;

in which R and R are each selected from the group consisting of hydrogenand alkyl as defined above or l I R R in which n is to 4, inclusive, andR is hydrogen and alkyl defined as above, or R is in which n is definedas above and R and R are each selected from the group consisting ofhydrogen and alkyl as defined above or together is pyrrolidino orpiperidino; wherein R and R are selected from the group consisting ofhydrogen, fluoro, chloro, bromo, iodo, amino, nitro, cyano, alkyldefined as above, trifluoromethyl, and alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, and alkanoylamino, in which the carbon moiety is of 1 to3 carbon atoms, inclusive, and dialkylamino in which alkyl is defined asabove.

The preferred compounds of this invention are those wherein X isselected from the group consisting of oxygen, sulfur,

s in which R and R are selected from the group consisting of hydrogen,alkyl of 1 to 3 carbon atoms, inclusive, and N-R in which R is selectedfrom the group consisting of hydrogen alkyl, defined as above,

in which n is 1 to 4, inclusive, and R is hydrogen and alkyl defined asabove, or R is in which R, and R are selected from the group consistingof hydrogen and alkyl as defined above, or

together is pyrrolidino or piperidino; wherein R is selected from thegroup consisting of hydrogen, alkyl, as defined above, hydroxymethyl,

in which n is 0 to 4 inclusive, and R and R are each selected from thegroup consisting of hydrogen and alkyl as defined above, or

together is pyrrolidino or piperidino; wherein R and R are selected fromthe group consisting of hydrogen, fluoro, bromo, chloro, nitro, cyano,alkyl defined as above, trifluoromethyl, and alkylthio, in which thecarbon moiety is of l to 3 carbon atoms, inclusive.

The most desirable compounds of formula III are those wherein X isselected from the group consisting of oxygen, sulfur, CH and NR in whichR is selected from the group consisting of hydrogen, methyl, ethyl,

s in which n is 1 to 3, inclusive, and R and R are each selected fromthe group consisting of hydrogen, methyl or ethyl, or

together is pyrrolidino; wherein R is selected from the group consistingof hydrogen, methyl, ethyl, hydroxymethyl,

in which n is 0 to 3, inclusive and R and R are each selected from thegroup consisting of hydrogen, methyl and ethyl; wherein R and R areselected from the group consisting of hydrogen, fluoro, chloro, nitro,trifluoromethyl, and alkylthio in which alkyl is defined as above.

The invention also embraces the pharmacologically acceptable acidaddition salts and N-oxides of the compounds of formula 111 above.

The process of this invention comprises: heating a thio compound offormula I with a selected carboxylic acid halide or anhydride to obtainthe triazole compound II and, if desired, to subject compound II toconventional processes to obtain compounds of formula III.

DESCRIPTION OF THE PREFERRED EMBODIMENT Lower alkyl groups of 1 to 3carbon atoms, inclusive, are exemplified by methyl, ethyl, propyl, andisopropyl.

The carbon chain moiety of alkoxy, alkylsulfinyl, alkylsulfonyl, andalkylthio, which is of 1 to 3 carbon atoms, inclusive, can be defined aslower-alkyl of 1 to 3 carbon atoms, inclusive, above.

The group CnH n wherein n is 1 to 4 comprises The alkanoylamino group of1 to 3 carbon atoms con- SlStS f fOIITlamldO acetamido and propionamido.

The compounds of formula III and the pharmacologically acceptable acidaddition salts are useful central nervous system agents for the controlof depression and anxiety in mammals and birds.

For the control of depression the compounds of formula III and thepharmacologically acceptable acid addition salts can be used in dosagesof 0.1 to 5.0 mg./kg. in oral or injectable preparations to alleviatedepression occurring in stressful situations in the same manner asimipramine, amitriptylene and other antidepressants. Such situations arethose, for example, when animals are changing ownership or aretemporarily put into kennels while their owners are absent from home.

For the control of anxiety the compounds of formula III and thepharmacologically acceptable acid addition salts can be used in dosagesof 0.01 to mg./kg. in oral and injectable preparations to alleviatetension and anxiety in mammals or birds in the same way as doxepine andother antianxiety agents. Such stressful situations arise, for example,when animals are in travel.

Acid addition salts of the compounds of formula III can be made, such asthe fiuosilicic acid addition salts which can be applied as mothproofingagents, and salts with trichloroacetic acid, useful as herbicidesagainst Johnson grass, Bermuda grass, yellow and red foxtail, and quackgrass.

The pharmaceutical forms of compounds of formula III and salts thereofcontemplated by this invention include pharmaceutical compositionssuited for oral, parenteral, and rectal use, e.g., tablets, powderpackets, cachets, drages, capsules, solutions, suspension, sterileinjectable forms, suppositories, bougies, and the like. Suitablediluents or carriers such as carbohydrates, lactose, proteins, lipids,calcium phosphate, cornstarch, stearic acid, methylcellulose and thelike may be used as carriers or for coating purposes. Water or oils suchas coconut oil, sesame oil, safflower oil, cottonseed oil, and peanutoil, may be used for preparing solutions or suspensions of the activedrug. Sweetening, coloring, and flavoring agents may be added.

For mammals food premixes with starch, oatmeal, dried fishrneat,fishmeal, flour, and the like can be prepared.

The starting materials of this invention dihydrodibenzoazepinethiones Iare either known or can be synthesized by known procedures e.g. byrefluxng the corresponding amides with phosphorus pentasulfide, asfurther illustrated in the Preparations.

In carrying out the process of this invention, a selected thione I, isheated with a carboxylic acid hydrazide to about 200 for a period of 30minutes to 4 hours. Product II which is thus obtained, is isolated andpurified by conventional means, e.g. extraction, filtration,chromatography or crystallization.

Alternatively the thione-starting material I can be treated withhydrazine or hydrazine hydrate at temperatures between -100 C. with orwithout a solvent such as ethanol or other alkanol, ether,tetrahydrofuran, benzene or the like for 1 to 4 hours to give thecorresponding intermediate IV:

R3 I H A IIQH NH2 8' wherein X, R R are defined as above, compound IVcan be condensed with an acid halide of the formula wherein R' isdefined as R herein above, when n is only 1-4, and X" is bromine orchlorine to give the corresponding compound of formula II.

If ethyl orthoformate is used, a Z a-unsubstituted 9H-dibenzo[c,f] striazolo[4,3 a]azepine, -diazepine, -oxazepine or -thiazepine isobtained which can he brominated and the resulting bromo compound can beused as intermediate for additional I l-substituted compounds of formulaIII as shown in the Examples.

The following preparations and examples are illustrative of theprocesses and products of the present invention, but are not to beconstrued as limiting.

Preparation 1 .6 5 H) -morphanthridinethione A mixture of6(5H)-morphanthridinethione (30 g., 0.144 mole), phosphorus pentasulfide(33.5 g. 0.158 mole) and 1200 ml. of pyridine was heated at refluxtemperature for 23 hours and the pyridine was then evaporated. Methylenechloride and water were added, and the organic layer was separated (somesolid was present), washed with aqueous sodium bicarbonate until only atrace of solid was present, then with saturated salt solution, driedover anhydrous magnesium sulfate and evaporated. Trituration of theresidue with methanol gave 28.8 g. of 6(5I-I)-morphanthridinethione ofmelting point 218219 C. Crystallization from methylene chloridemethanolgave the product as pale yellow rods; the melting point was unchanged.

Anal.

Calcd. for C H N C, 74.63; H, 4.92; N, 6.22; S,

14.23. Found: C, 74.94; H, 5.07; N, 6.08; S, 14.25.

Preparation 2.5, 10-Dihydro-1 1H-dibenzo[b,e] [1,4] diazepine- 1l-thione A mixture of 5,10-dihydro-1lI-I-dibenzo[b,e][l,4]diazepin-ll-one (10 g., 0.0476 mole), phosphorus pentasulfide (9.3g., 0.0525 mole) and 365 ml. of pyridine was heated at refluxtemperature for 3 hours and allowed to stand overnight. The pyridine wasevaporated, and the residue was shaken with 250 ml. each of water andchloroform. The resulting suspension was filtered to remove solidproduct. After filtration the chloroform layer was separated from theaqueous layer, washed with water and saturated salt solution, dried overanhydrous magnesium sulfate and evaporated. The residue was combinedwith the solid obtained above and crystallized from methanol. Two cropsof 5,10-dihydro-11I-I-dibenzo[b,e] 1,4] diazepin-l l-thione wereobtained; yield, 9.01 g. (84% of theory), melting point 257-259 C.

Preparation 3.Dibenzo [b,f] [1,4]oxazepine-11(10H)- thione A mixture ofdibenz[b,f] [1,4]oxazepin-1l(10I-I)-one (21.6 g., 0.1 mole), phosphoruspentasulfide (23.4 g., 0.105 mole) and 850 ml. of pyridine was heated atreflux temperature for 4 hours and the pyridine was evaporated in vacuo.The residue was stirred with chloroform, and 500 ml. of saturatedaqueous sodium bicarbonate solution was added. The resulting suspensionwas filtered and the solid was discarded. The filtrate was separatedinto layers, and the organic layer was washed successively with aqueoussodium bicarbonate and with saturated salt solution, dried overanhydrous magnesium sulfate and evaporated. The residue was crystallizedfrom chloroformmethanol; 14.6 g. of dibenzo [b,f][1,4]oxazepine-11(1OH)- thione was obtained as pale yellow needles whichmelted at 194-195 C. Recrystallization did not alter the melting point.

9 Anal.

Calcd. for C H NOS: C, 68.69; H, 3.99; N, 6.16;

3, 14.11. Found: C, 68.50; H, 3.93; N, 6.30; S, 13.77.

Preparation 4 .-Dibenzo [b,f] 1,4]thiazepine-11 (10H)- thione /S\ 1 ft sn Preparation 5 .7-Chloro-5, IO-dihydro-l lH-dibenzo- [b,e][l,4]diazepine-11-thione A mixture of7-chloro-5,10-dihydro-11H-dibenzo[b,e] [l,4]diazepin-11-one (30.5 g.,0.125 mole), phosphorus pentasulfide (27.8 g., 0.131 mole) and one 1. ofpyridine was heated at reflux temperature for 4 hours and the pyridinewas evaporated in vacuo. The residue was stirred for 1 hour with one 1.each of saturated aqueous sodium bicarbonate and methylene chloride andfiltered to remove some solid product. The organic layer of the filtratewas washed successively with sodium bicarbonate solution and withsaturated salt solution, dried over anhydrous magnesium sulfate andevaporated. The residue was combined with the solid obtained above andtriturated with hot chloroform and methanol; 12.2 g. of7chloro5,10-dihydro-1lH-dibenzo[b,e] [1,4]diazepine-1l-thione wasobtained of melting point 274-275 C. Concentration of thechloroform-methanol washings afforded an additional 8.4 g. of producthaving the same melting point. Recrystallization fromdimethylformarnide-water gave an analytical sample in the form of paleyellow needles of melting point 276-277 C.

Preparation 6 .-5 10-Dihydro-5 -methyl-l lH-dibenzo- [b,e][1,4]diazepine-11-thione A mixture of5,10-dihydro-5-methyl-11H-dibenzo[b,e] [1,4]diazepine-11-one (6.1 g.,0.0272 mole), phosphorus pentasulfide (6.51 g., 0.0286 mole) and 175 ml.of pyridine was evaporated in vacuo. The residue was stirred for 1 hourwith one 1. each of saturated aqueous sodium bicarbonate and methylenechloride and filtered to remove some solid product. The organic layer ofthe filtrate was washed successively with sodium bicarbonate solutionand with saturated salt solution, dried over anhydrous magnesium sulfateand evaporated. The residue was combined with the solid obtained aboveand triturated with hot chloroform and methanol; 12.2 g. of7-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione wasobtained of melting point 274-275 C. Concentration of thechloroform-methanol washings afforded an additional 8.4 g. of producthaving the same melting point. Recrystallization fromdimethylformamide-water gave an analytical sample in the form of paleyellow needles of melting point 276-277 C.

Preparation 7 .5 1 0-Dihydro-5 -methyl-1 lH-dibenzo [b,e]1,4]diazepine-11-thione A mixture of5,10-dihydro-5-methyl-l1H-dibenzo[b,e] [1,4]diazepin-11-one (6.1 g.,0.0272 mole), phosphorus pentasulfide (6.51 g., 0.0286 mole) and 175 ml.of pyridine was heated at reflux temperature for 3.75 hours and thepyridine was then evaporated in vacuo. The residue was shaken withchloroform and saturated aqueous sodium bicarbonate. The resultingsuspension was filtered to give solid A. The chloroform layer of thefiltrate was Washed successively with saturated aqueous sodiumbicarbonate and with saturated salt solution, dried over anhydrousmagnesium sulfate, and evaporated. The residue was crystallized frommethylene chloride-methanol to give 3.5 g. of5,10-dihydro-5-methyl-11H-dibenzo[b,e][1,4]diazepin-ll-thione of meltingpoint 217-218 C., which was unchanged after recrystallization. A secondcrop weighed 0.8 g. and melted at 2l4-215 C. A third crop weighed 0.25g. and melted at 216-217.

Solid A was shaken with methylene chloride and 10% sodium hydroxide andprocessed as above to give an additional 1.5 g. melting at 216-217 C.

Anal.

Calcd. for C H N S: C, 69.96; H, 5.03; N, 11.66;

S, 13.34. Found: C, 69.79; H, 5.02; N, 11.37; S, 13.29.

Example 1 .--3-methyl-9H-dibenzo [b,f] -s-triazolo [4,3-d] [1,4]diazepine A mixture of 5,10 dihydro-11H-dibenzo[b,e] [1,4]diazepine-ll-thione prepared as described above (4.2 g.; 0.0186 mole) andacethydrazide (13.8 g.; 0.186 mole) was kept in a preheated oil bath for50 minutes at 200 C. using a take-01f condenser. It was cooled, waterand chloroform were added and the suspension was filtered: 3.75 g. (81%yield) of 3-methyl-9H-dibenzo[b,f]-s-triazolo[4,3-d] [1,4]diazepine ofmelting point 330 C. was obtained which did not change oncrystallization from tetrahydrofuran.

Anal.

Calcd. for C H N C, 72.56; H, 4.87; N, 22.57, Found: C, 72.05; H, 4.66;N, 22.81.

Example 2.9H-Dibenzo [b,f] -s-triazolo [4,3-d] [1,4] diazepine In themanner given in Example 1, 5,10-dihydro-11H- dibenzo[b,e] [1,4]diazepine1 thione was condensed at about 200 C. with formic acid hydrazide togive 9H-dibenzo[b,f] s triazolo[4,3-d][1,4]diazepine of melting point283-285 C.

Example 3 .6, 12-dichloro-9H-dibenzo[b,f ]-striazolo [4,3-d] [1,4]diazepine In the manner given in Example 1, 2,8-dichloro-5,10-dihydro-11H-dibenzo[b,e] [1,4] diazepine 11 thione was condensed atabout 200 C. with formic acid hydrazide to give 6,12-dichloro 9Hdibenzo[b,f]-s-triazolo[4,3- d] [1-41diazepine.

Example 4.-7-Chloro-3-methyl-9H-dibenzo-striazolo [4,3-d] 1,4]diazepineIn the manner given in Example 1, 7-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine 11 thione was condensed at 200 C. withacethydrazide to give 7-chloro- 3 methyl-9H-dibenzo[b,f] striazolo[4,3-d][1,4]diazepine of melting point 309-310.

Example 5.3-Methyl-7,1l-difiuoro-9H-dibenzo[b,f]- s-triazolo [4,3-d][1,4] diazepine In the manner given in Example 1,3,7-difluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine 11 thione wascondensed at about 200 C. with acethydrazide to give3-methyl-7,l1-difluoro-9H-dibenzo[b,f] s triazolo[4,3- (1] [1,4]diazepine.

Example 6 .-6, l2-Dichloro-9H-dibenzo [c,f] -strizolo [4,3 -a] azepineIn the manner given in Example 1, 3,8-dichloro-5,10-dihydro-6H-dibenzo[b,e]azepine-6-thione was condensed at about 200 C.with formic acid hydrazide to give 6,12- dichloro-9H-dibenzo [c,f]-s-triazolo [4,3 -a] azepine.

1 1 Example 7 .6, l 2-dichloro-9,9-dimethyl-9H-dibenzo- [c,f] -s-triazol[4,3-a] azepine In the manner given in Example 1, 3,8-dichloro-11,11-dimethyl-5,l1-dihydro 6H dibenz[b,e]azepine-6-thione was condensed atabout 200 C. with formic acid hydrazide to give 6,12-dichloro 9,9dimethyl 9H dibenzo [c,f] -s-triazolo [4,3-a] azepine.

Example 8.6,l2-Dichl0ro-dibenzo[b,f]-s-triazolo[4,3-

d] [l,4]thiazepine In the manner given in Example 1, 2,8-dichlorodibenzo[b,f] [1,4]thiazepine-11(10H)-thione was condensed at about 200 C. withformic acid hydrazide to give 6,12- dichlorodibenzo [b,f] -s-triazolo[4,3-d] [1,4] thiazepine.

Example 9.6, l2-Dichlorodibenzo [b,f -s-triazolo [4,3-

d] [1,4] oxazepine In the manner given in Example 1, 2,8-dichlorodibenzo[b,f] [l,4]oxazepine-11(10H)thione was condensed at about 200 C. withformic acid hydrazide to give 6,12-dichlorodibenzo [b,f] -s-triazolo[4,3-d] [1,4] oxazepin.

Example 10.7,10-Diamino 3 [3-(dimethylamino)propyl]-9H-dibenzo [b,f]-s-triazolo [4,3-d] [1,4] diazepine In the manner given in Example 1,4,7-diamino-5,10 dihydro-11H-dibenzo[b,e] [1,4]diazepine 11 thione wascondensed at about 200 C. with 4 (dimethylamino) butyric acid hydrazideto give 7,10-diarnino-3-[3-(dimethylamino)propyl] (9H) dibenzo[b,f] striazolo[4,3- d] [1,4] diazepine.

Example 11 .12-Amino-7-bromo-3- cyanomethyl -9H- dibenzo [c,f]-s-triazolo [4,3-a] azepine In the manner given in Example 1,8-amino-2-bromo- 5,11-dihydro-6H-dibenzo[b,e]azepine 6 thione wascondensed at about 200 C. with cyanoacetic acid hydrazide to give12-amino-7-bromo 3 (cyanomethyl) 9H dibenzo [c,f] -s-triazolo [4,3-a]azepine.

Example 12.-3-Ethyl-12-chlor0dizenbo [b,f]-s-triazolo 3,4-d] [1,4]oxazepine In the manner given in Example 1, 2-chlorodibenzo[b, f][1,4]oxazepine-11(1OH)-thione was condensed at about 200 C. withpropionic acid hydrazide to give 3-ethyl-12- chlorodibenzo [b,f]-striazolo[3,4-d] [1,4]oxazepine.

Example 13.7-Dipropylamino-1 1-iodo-3 -methyldibenzo [b,f] -s-triazolo[4,3 -d] [1,4] thiazepine In the manner given in Example 1,3-dipropylamino-7- iododibenzo[b,e][1,4]thiazepin 11(10H) thione wascondensed at about 200 C. with acethydrazide to give11-dipropylamino-7-iodo 3 methyldibenzo[b,f]-s-triazolo [4,3-d][1,4]thiazepine.

Example 14.9-[3-(Dimethylamino)propyl] 3 methyl- 9I-I-dibenzo [b,f]-s-triazolo [4,3 -d] [1,4] diazepine Sodium hydride (0.21 g.; mmoles of57% dispersion in mineral oil) Was added to a solution of 3-methyl-9H-dibenzo[b,f] s triazolo[4,3-d] [1,4]diazepine 1.24 g.; 5 mmoles) in 50ml. of dimethylformamide, the mixture was stirred at room temperaturefor 25 minutes and then heated at 95 C. for 25 minutes. After another 15minutes at room temperature, 3-(dimethylamino)propyl chloride (0.65 g.;5 mmoles in 0.65 g. of xylene) was added and the mixture was heated at95 C. for 21 hours. It was evaporated and the residue shaken with 25 ml.each of ether and water. The resulting suspension was filtered to give0.6 g. of starting compound. The filtrate was separated into layers. Theaqueous layer was extracted with methylene chloride (2X ml.) and thecombined organic extract was washed with saturated salt solution, driedover anhydrous magnesium sulfate and evaporated. The residue wastriturated with ether to give 0.38 g. of 9-[3-(dimethylamino)propyl] 3methyl 9H dibenzo [b,f]-s-triazolo[4,3-d] [1,4]diazepine of meltingpoint 165- 12 167 C., raised to 170.5171.5 on recrystallization fromethyl acetate.

Anal.

Calcd. for C H N C, 72.04; H, 6.95; N, 21.01. Found: C, 71.82; H, 7.29;N, 21.12. Example 15.--9- [2- dimethylamino ethyl] -3-methyl-9H- dibenzo[b,f] -s-triazolo [4,3-d] [1,4]diazepine In the manner given in Example14, 3-methyl-9H-dibenzo[b,f]-s-triazolo[4,3-d] [1,4]diazepine was firstreacted with sodium hydride and then with Z-(dimethylaminoethyl)chlorideto give 9-[2-(dimethylamino)ethyl]- 3-methyl 9H dibenzo[b,f] striazolo[4,3-d] [1,4]diazepine of melting point 2152l6 C.

Example 1 6--9- [2- (dimethylamino ethyl] -9H-di benzo[-b,f]-s-tri-azolo [4,3-d] [1,4] diazepine In the manner given inExample 14, 9H-dibenzo[b,f]- s-triazolo[4,3-d] [1,4]diazepine was firstreacted with sodium hydride and then with Z-(dimethylamino)ethylchloride to give9-[2-(dimethylamino)ethyl]-9H-dibenzob,'f]-s-triazolo[4,3-d][l,4]diazepine of melting point '137-138" C.

Example 17-9- 3 (dimethylam ino)propyl] -9H-dibenzo[b,f]-s-triazolo[4,3-d] [l,4]diazepine In the manner given in Example14, 9H-dibenzo[b,f]- s-triazolo[4,3-d] [1,4]diazepine was first reactedwith sodium hydride and then with 3-(dimethylamino)propyl chloride togive 9-[3-(dimethylamino)propyl]-9H-dibenzo [b,f] striazol'o[4,3-d1diazepine of melting point 134.5-136.

Example 1 8--7-Chloro-9- [3- (dimethylamino propyl] 3-methyl-9Hdi'benzo[b,f] -s-triazolo [4,3-d] diazepine In the manner given in Example 14,7-Chloro-3-methyl- 9H-dibenzo [b,f] -s-triazolo [4,3-d] [1,4]diazepinewas first reacted with sodium hydride and then with3-(dimethylamino)propyl chloride to give7-chloro-9-[3-dimethylamino)propyl-3-methyl-9H-dibenzo[b,f] striazolo[4, 3-d][l,4]diazepine of melting point l-l8l C.

Example 19--11-Hydrazino-5H-di-benzo[b,e] [1,4] diazepine hydrochlorideTo a stirred solution of 5,10-dihydro-1lH-dibenzo-[b,e][1,4]diazepine-1l-thione (42.1 g., 0.0186 mole) in dry methanol(1,500 ml.) was added hydrazine hydrate (37.4 g., 0.743 mole, A nitrogenbubbler was used to aid in the removal of the hydrogen sulfide formed.The reaction mixture was refluxed via steam bath for l /2hours andconcentrated in vacuo. The oil was mixed with water and extracted withbenzene. The benzene was washed with water several times, then acidifiedwith aqueous hydrogen chloride. The hydrochloride salt was collected byfiltration, Washed with benzene and dried to give 37.0 g. (77%), whichsoftens at -140" then completely melts at 25l254. The aqueous layer ofthe filtrate was made basic with aqueous sodium hydroxide and extractedwith chloroform. The chloroform was washed with water, dried (sodiumsulfate) and concentrated in vacuo. The oil was dissolved in ethylacetate and acidified with ethanolic hydrogen chloride to give 2.42 g.,melting point 250254 and 1.31 g., melting point 260268 of additionalproduct (overall yield 84% The analytical sample had a melting point253255.

Anal. Calcd. for C H N Cl: C, 59.88; H, 5.03; N, 21.49; Cl, 13.60.Found: C, 58.02; H, 5.01; N, 21.20; Cl, 13.13.

Example 20.1l-(1-chloroacetylhydrazin-Z-yl)-5H- dibenzo[b,e] [1,4]diazepine hydrochloride 15 ml. dry tetrahydrofuran and cooled in an icebath. Chloroacetyl chloride (0.565 g.; 0.005 mole) was mixed with m1. oftetrahydrofuran and added slowly to the reaction mixture. A gummy solidappeared which formed a precipitate after stirring for one hour. Themixture was cooled and then stirring continued for 2 hours. The reactionflask was filtered, washed with chloroform, and then ether. The solidobtained was dried and used without further purification.

Example 21.3-Chloromethyl-9H-dibenzo [b,f]-s-tri-azolo[4,3-d]-s-tri-azolo[4,3-d] [1,4] diazepine 11-(l-chloroacetylhydrazin-Z-yl) 5Hdibenzo[b,e]- [1,4]diazepine hydrochloride (1.39 g., 0.004 mole) wasmixed with acetic acid and refluxed under nitrogen at 123 in an oilbath. The reaction was stirred for 30 minutes, concentrated in vacuo andthen diluted with water. The aqueous solution was neutralized withsodium bicarbonate and extracted with chloroform (precipitate isinsoluble in chloroform). Methanol was added and the precipitate wentinto the chloroform layer. The chloroform methanol layer was washed withwater and then with brine, dried over sodium sulfate and concentrated.The solid was crystallized with chloroform methanol and ethyl acetate togive 0.47 g. of3-chloromethyl-9H-dibenzo[b,f]-s-triazolo[4,3-d][1,4]diazepine ofmelting point 280295. Further crops of 0.36 g. and 0.105 g. wereobtained.

Anal. Calcd. for C H N Cl: C, 63.72; H, 3.92; N, 19.82; Cl, 12.54.Found: C, 63.31; H, 3.98; N, 19.67; Cl, 12.72.

Example 22.2- [2-(2-Diethylamino ethyl]-3-methyl- 9H-dibenzo b,f]-s-triazolo [4,3-d] 1,4] diazepine In the manner given in Example 14,3-methyl-9H-dibenz0[b,f]-s-triazolo[4,3-d][1,4]diazepine was reactedwith sodium hydride and then with diethylaminoethyl bromide to give9-[2(diethylamino)ethyl]-3methyl-9H dibenzo [b,f] -s-tniazolo [4,3-d][1,4] diazepine.

Example 23.-6,12-Dichloro-9-[2 (dipropylamino) ethyl] 3-methyl-9Hdibenzo[ bj] s -triazolo[4,3-d][1,4]- diazepine In the manner given inExample 14, 6,12-dichloro-9H- dibenzo[b,f]-s-triazolo [4,3-d][1,4]diazepine was reacted with sodium hydride and then with(Z-dipropylamino) chloride to give 6-12-dichloro 9 [2 (dipropylamino)-ethyl] 3 methyl 9H dibenzo[b,f]-s-triazolo[4,3-d]- [-1,4]diazepine.

In the manner give in Example 14, 7,1l-difiuoro-3- methyl-9H-dibenzo[b,'f]-s-triazolo [4,3 d] [1,4] diazepine was reacted with sodiumhydride and then with ethyl iodide to give7,11-difluoro-9-ethyl-3-methyl-9H-dibenzotri'azolo [4,3-d] diazepine.

Example 25.-7-Chloro 3,9 bis[2 (dimethylamine)- ethyl]-9H-dibenzo[b,f] striazolo[4,3-d] [1,4]diazepine In the manner given in Example 14,7-chloro-3-[2-(dimethylamino)ethyl] 9H dibenzo[b,f] s triazolo[4,

3-d] [1,4]diazep ine was reacted with sodium hydride and then with2-(d-imethylamino)ethyl bromide to give 7-chloro-3,9-bis[2-(dimethylamino)ethyl] 9H dibenzo [b,f]-s-triazolo[4,3-d] [1,4] diazepine.

Example 26.3-Bromo-9H-dibenzo[b,f] -stri 1 1,4]diazepine LA stirredmixture of 9H-dibenzo[b,f]-s-triazolo[4,3-d] [1,4]diazepine,N-brornosuccinimide and carbon tetrachloride was refiuxed, undernitrogen for 4 hours cooled and concentrated in vacuo. The residue wasmixed With Water and extracted with chloroform. The extract was driedover anhydrous potassium carbonate and concen- 14 trated.Crystallization of the residue from ethyl acetate gave 3 bromo 9Hdibenzo[b,f] s triazolo[4,3-d] [1,4] diazepine.

Example 2 7.3 -diethylamino-9H-dibenzo [b,f] -s-triazo1 [1,4] diazepineA mixture of 3 bromo 9H dibenzo[b,f] s triazolo[4,3-d] [1,4]diazepineand diethylamine was refluxed for 18 hours and then poured into water.The mixture was made alkaline with sodium bicarbonate and then extractedwith chloroform. After evaporation of the chloroform extracts 3diethylamino 9H dibenzo[b,f] s-triazolo[4,3-d][l,4]diazepine wasobtained which was purified by crystallizations from ethanol-water.

Example 28.-3-Cyanomethyl-9H-dibenzo [b,f] -striazolo [4,3-d][1,4]diazepine 3-Chloromethyl 9H dibenzo[b,f] s triazolo[4,3'd][1,'4]diazepine was added, under nitrogen to a stirred solution ofsodium cyanide in dry dimethylsulfoxide which had been warmed in a bathmaintained at 84 C. After 30 minutes the mixture was cooled, and pouredinto water; the product was extracted with chloroform. The extract waswashed with brine, dried over anhydrous potassium carbonate andconcentrated. The residue was crystallized from ethylacetate-Skellysolve B hexanes to give 3 cyanomethyl 9H dibenzo[b,f] striazolo- [4,3-d] [l,4]diazepine.

Example 29.3-Cyan 9H-dibenzo [b,f] -s-triaz 1 [1,41diazepine In themanner given in Example 28, 3-chloro-9H-dibenzo[b,f]-s-triazolo[ 4,3-d][1,4]diazepine was treated with potassium cyanide to give3-cyano-9H-dibenzo[b,f]- s-triazolo[4,3-d] [1,4]diazepine.

Example 30.-9H-Dibenzo [b,f] -s-triazolo [4,3-d] [1,4]diazepin-3-aceticacid methyl ester A mixture of3-cyanomethyl-9H-dibenzo[b,f]-s-triazolo[4,3-d][1,4]diazepine, methanoland ether was cooled in a salt-ice bath and the reaction mixturesaturated with a stream of anhydrous hydrogen chlorine during 15minutes. The mixture was allowed to warm slowly to ambient temperatureand stand for 18 hours. It was then poured into water, neutralized withsodium bicarbonate and extracted with chloroform. The extract was washedwith brine, dried and concentrated. The residue was crystallized frommethanol-ethyl acetate to give 9H- dibenzo [b,f] -s-triazolo[4,3-d][1,4] diazepin-3-acetic acid methyl ester.

Example 31 .-6,12-Dichloro-3-[1-methyl-piperidin-2-yl]- 9H-dibenz0[b,f]-s-triazolo [4,3-d] [1,4] diazepine In the manner given in Example1, 2,8-dichloro'5,10 dihydro 11H dibenzo[b,e] [1,4]diazepine-11-thionewas condensed with [(1-methyl)piperidinyl]formic acid hydrazide at about200 C. to give 6,12-dichloro 3 [1- rnethylpiperidin 2 yl] 9Hdibenzo[-b,f] s triazolo- [4,3-d] [1,4] diazepine.

Example 32.--3 ('Dimethylamino) methyl] -9H'dibenzo- [b,f 1 's-triazolo[4,3-d] [1,4] diazepine 15 Anal. Calc. for C H N C, 70.08; H, 5.88; N,24.04. Found: C, 70.40; H, 5.84; N, 24.51.

Example 3 3 .3-[ (Diethylamino) methyl] -9H-dib enzo- [b,f] -s-triazolo[4,3-d] [1,4] diazepine To a stirred solution of3-chloromethyl-9H-dibenzo- [b,f] s triazolo[4,3-d][1,4]diazepine (1.41g. 0.005 mole) in dry tetrahydrofuran (25 ml.) and methanol (5 ml.) wasadded potassium iodide (1.66 g.) and diethylamine (5 ml.) undernitrogen. The mixture was stirred at ambient temperature for 2 hr.,mixed with water and extracted with chloroform. The chloroform solutionwas washed with water, dried over sodium sulfate and concentrated invacuo. The oil was crystallized from methanol chloroform ethyl acetateto give 1.35 g. (85%) of 3-[(dicthylamino)methyl]-9H dibenzo[b,f] striazolo[4,3-d][l, 4]diazepine of melting point 232-235. The analyticalsample had a melting point of 232-235".

Anal. Calcd. for C H N C, 71.44; H, 6.63; N, 21.93. Found: C, 70.95; H,6.70; N, 21.51.

Example 34.-(Pyrrolidinomethyl)-9H-dibenzo [b,f] -striazolo[ 4,3-d][1,4] diazepine To a stirred solution of 3-chloromethyl-9H-dibenzo [b,f]s triazo1o[4,3 d][1,4]diazepine (1.41 g., 0.005 mole) in drytctrahydrofuran (20 ml.) and methanol (5 ml.) was added potassium iodide(1.66 g.) and pyrrolidine (5 ml.) under nitrogen. The mixture wasstirred at ambient temperature for 2 hr., mixed with water and extractedwith chloroform. The chloroform was washed with water, dried over sodiumsulfate and concentrated in vacuo. The oil was crystallized frommethanol ethyl acetate to give 1.26 g. (80%), of melting point 10010=7of 3-(pyrrolidino-9H-dibenzo[b,f] s triazolo[4,3-d] [l,4]diazepine. Theanalytical sample had a melting point of 100-107 (foaming).

Anal. Calcd. for C19H19N5: c, 71.90; H, 6.03; N, 22.07; Found: c, 71.63;H, 6.26; N, 22.0.

Example 35.3- (Z-Chloroethyl) -9H-dibenzo [b,f] -striazolo [4,3-d][1,4]diazepine 11 Hydrazino 5H dibenzo[b,e] [1,4]diazepine hydrochloride(13.0 g., 0.05 mole) was dissolved in water, neutralized with aqueoussodium hydroxide and extracted with chloroform. The chloroform waswashed with water, dried over sodium sulfate and concentrated in vacuo.The oil was dissolved in dry tetrahydrofuran (200 ml.), under nitrogenand 3-chloropropionyl chloride (6.35 g., 0.05 mole) in tetrahydrofuran(50 ml.) was added slowly to the stirred solution. The reaction mixturewas stirred at ambient temperature for 2% hour. The hydrochloride saltof the adduct was collected by filtration, washed with ether and driedin a vacuum oven (40) to give 1.431 g.

This hydrochloride salt was combined with glacial acetic acid (150 ml.)and heated, under nitrogen in an oil bath at 120 for 15 minutes. Thereaction mixture was cooled and the precipitate collected by filtrationand washed with acetic acid. The precipitate was mixed with Water andchloroform, neutralized with aqueous sodium hydroxide and recollected byfiltration. The chloroform was separated, washed with water, dried oversodium sulfate and concentrated in vacuo.. These two residues wererecrystallized from methanol chloroform ethyl acetate to give 4.37 g.(37% melting point 90-92 of 3-(2-chloroethyl)-9Hdibenzo[b,f]-s-triazolo[4,3-d] [1,4]diazepine. The analytical sample hada melting point of 9497.5.

Anal.

Calcd. for C H N Cl: C, 64.75; H, 4.41; N, 18.88;

Cl, 11.95. Found; C, 65.88; H, 4.39; N, 19.90; Cl. 10.49.

1 6 Example 3 6 .-3- [Z-(Dimethylamino) ethyl] -9H-dibenzo [b,f]-s-triazolo [4,3-d] [1,4] diazepine To a stirred solution of3-(2-chloroethyl)-9H-dibenzo [b,f]-s-triazolo [4,3-d] [1,4]diazepine(1.48 g., 0.005 mole) in dry dimethylformarnide (25 ml.) was addedpotassium iodide (1.66 g.) and dimethylamine (4.745 g., in 5 ml.methanol) under nitrogen. The mixture was stirred at ambient temperaturefor 18 hr., mixed with water and extracted with chloroform. Thechloroform was washed with water, dried over sodium sulfate andconcentrated in vacuo. The oil was crystallized twice from methanolethyl acetate to give 0.48 g. of 3-[2-(dimethylamino)ethyl]9Hdibenzo[b,f] s triazolo[4,3-d][1,4-diazepine (32%), melting point161-165. The analytical sample had a melting point of 16l165.

Anal.

Calcd. for C H N C, 70.79; H, 6.27; N, 22.94. Found: C, 70.70; H, 6.33;N, 23.11.

Example 37.-3- (2-Pyrrolidinoethyl)-9H-dibenzo[b,f] striazolo [4,3-d][1,4] diazepine To a stirred solution of 3-(2-chloroethyl)-9H-dibenzo[b,f] s triazolo[4,3 d][1,4]diazepine (1.48 g., 0.005 mole) in drydimethylformamide (25 ml.) was added potassium iodide (1.66 g.) andpyrrolidine (5 ml.) under nitrogen. The mixture was stirred at ambienttemperature for 18 hr., mixed with water, dried over sodium sulfate andconcentrated in vacuo. The oil was crystallized twice from methanolethyl acetate to give 0.71 g. (43%) of 3- (2-pyrrolidinoethyl)-9Hdibenzo[b,f] s triazolo[4,3- d] [1,4] diazepine of melting point 208210.The analytical sample had a melting point of 208-210.

Anal.

'Calcd. for C H N C, 72.48; H, 6.39; N, 21.13. Found: C, 72.96; H, 6.55;N, 21.53.

Example 38.3-Vinyl-'9H-dibenzo [b,f] -s-triazolo [4,3-d] [1,4] diazepineTo a stirred solution of 3-(2-chloroethyl)-9H-dibenzo [b,f]-s-triazolo[4,3 d] [l,4]diazepine (1.26 g., 0.00425 mole) in dry dimethylformamide(25 ml.) was added potassium iodide 1.66 g.) and diethylamine (5 ml.)under nitrogen. The mixture was stirred at ambient temperature for 18hr., mixed with water and extracted with chloroform. The chloroform waswashed with water, dried over sodium sulfate and concentrated in vacuo.The residue was collected, washed with ethyl acetate and recrystallizedfrom methanol ethyl acetate to give 0.545 g. (38%) of 3-vinyl-9H-dibenzo[b,f] s triazolo [4,3 d] [1,4]diazepine of melting point300. The analytical sample had a melting point of 300.

Anal.

Calcd. for C H N C, 73.82; H, 4.65; N, 21.53. Found: C, 73.40; H, 4.69;N, 20.79.

Example 39.3- 3-Chloropropyl -9H-dibenzo [b,f] -striazolo [4,3-d] [1,4]diazepine ll-Hydrazino-SH dibenzo[b,e][1,4]diazepine hydrochloride(13.08 g., 0.05 mole) was dissolved in water, neutralized with aqueoussodium hydroxide and extracted with chloroform. The chloroform waswashed with water, dried over sodium sulfate and concentrated in vacuo.The oil was dissolved in dry tetrahydrofuran (150 ml.) under nitrogenand 4-chlorobutyryl chloride (7.05 g., 0.05 mole) in dry tetrahydrofuran(50 ml.) was slowly added to the stirred solution. The reaction mixturewas stirred at ambient temperature for 4 hr. The hydrochloride salt ofthe adduct was collected by filtration, washed with ether and dried in avacuum oven (40) to give 14.123 g.

This hydrochloride salt was combined with glacial acetic acid ml.) andheated under nitrogen in an oil bath at for 15 minutes. The reactionmixture was cooled and the precipitate collected by filtration andwashed with acetic acid. The filtrate was concentrated in vacuo, mixedwith water, neutralized with aqueous sodium hydroxide and extracted withchloroform. The collected precipitate from above was mixed with waterand chloroform, neutralized with aqueous sodium hydroxide and thechloroform separated. The two chloroform solutions were combined, washedwith water, dried over sodium sulfate and concentrated in vacuo. Theresidue was dissolved in methanol chloroform decolorized with Darco andcrystallized by concentrating and adding ethyl acetate to give 8.76 g.of 3-(3-chloropropyl)-9H-dibenzo[b,f]-s-triazolo- [4,3-d][1,4]diazepinof melting point 175177 and 2.28 g., melting point 171-172 (overallyield 92%). The analytical sample had a melting point of 173175 C.

Anal.

Calcd. for C H N Cl: C, 65.69; H, 4.86; N, 18.03;

'Cl, 11.41. Found: C, 65.38; H, 5.00; N, 18.04; Cl, 11.60.

Example 40.3-[3-(Dimethylamino)propyl] -9H-dibenzo [b,f] -s-triazolo[4,3] [1,4 diazepine dihydrochloride To a stirred solution of3-(3-chloropropy1)-9H-dibenzo [b,f] s triazolo[4,3-d][l,4]diazepine(1.55 g., 0.005 mole) in dry dimethylformamide (25 ml.) was addedpotassium iodide (1.66 g.) and dimethylarnine (15 ml. of a saturatedmethanol solution) under nitrogen. The mixture was stirred at ambienttemperature for 40 hr. and at 50 for 18 hr. to complete the reaction.The mixture was mixed with water and extracted with chloroform. Thechloroform Was washed with water, dried over sodium sulfate andconcentrated in vacuo. The oil was dissolved in ethyl acetate acidifiedwith methanolic hydrogen chloride and recrystallized from methanol ethylacetate to give 1.74 g. of 3-[3-(dimethylaminopropyl1 9Hdibenzo[b,f]-s-triazolo[4,3 d][1,4]diazepine dihydrochloride (94%) ofmelting point 290293. The analytical sample had a melting point of291296.

Anal.

Calcd. for C H N Cl C, 55.13; H, 6.80; N, 18.91;

Cl, 19.15. Found: C, 57.47; H, 5.90; N, 17.89, C1, 17.99.

Example 41.3-[3- (diethylarnino)propyl] -9H-dibenzo- [b,f] -s-triazolo[4,3-d] [1,4] diazepine dihydrochloride To a stirred solution of3-(3-chloropropyl)-9H-dibenzo[b,f]-s-triazolo[4,3-d][1,4]diazepine (1.55g., 0.005 mole) in dry dimethylformamide (25 ml.) was added potassiumiodide (1.66 g.) and diethylamine (5 ml.) under nitrogen. The mixturewas stirred at ambient temperature, was mixed with Water and extractedwith chloroform. The chloroform was Washed with water, dried over sodiumsulfate and concentrated in vacuo. The oil was dissolved in ethylacetate, acidified with methanolic hydrogen chloride and recrystallizedfrom methanol-ethyl acetate to give 1.30 g., of3-[3-(diethylamino)propyl]- 9H-dibenzo [b,f]-s-triazo1o[4,3-d] [1,4]diazepine dihydrochloride of melting point 278-283 and 0.21 g., ofmelting point 275-285 (overall yield 72%). The analytical sample had amelting point of 275-280.

Anal.

Calcd. for C H N Cl C, 59.99; H, 6.47; N, 16.66;

C1, 16.87. Found: C, 59.32; H, 6.37; N, 16.10; Cl, 16.65.

Example 42 .-3-( 3-Pyrrolidinopropyl) -9H-dibenzo [b,f] s-triazol[4,3-d] [1,41diazepine dihydrochloride To a stirred solution of3-(3-chloropropyl)-9H-dibenzo[b,f]-s-triazolo[4,3-d][1,4]diazepine (1.55g. 0.005 mole) in dry dimethylformamide (25 ml.) was added potassiumiodide (1.66 g.) and pyrrolidine (5 ml.) under nitrogen. The mixture wasstirred at ambient temperature for 40 hr., mixed with water andextracted with chloroform. The chloroform was washed with water, driedover Anal.

Calcd. for C H N Cl C, 60.28; H, 6.02; N, 16.74;

Found: C, 59.80; H, 5.93; N, 17.04; Cl, 16.85.

Example 43 .-3- (Z-Pyridyl) -9H-dibenzo [c,f] -s-triazolo- [4,3-a]azepine A mixture of 6(5H)-morphanthridinethione (2.25 g., 0.01 mole)and picolinic acid hydrazide (13.7 g.; 0.1 mole) was kept in a preheatedoil bath at 155160 C. for 15 minutes and then at 200-215 C. for 45minutes using a take-off condenser. The mixture was cooled, dissolved inmethylene chloride and water and. the resulting suspension was filteredto give 4 g. of solid A, and filtrate B. Solid A was discarded.

FiItrate B was separated into layers over anhydrous magnesium sulfateand the organic layer was washed with saturated salt solution, driedover anhydrous magnesium sulfate and evaporated. The residue (5.6 g.)was chromatographed on 5 60 g. of silica gel using 5% methanol-%chloroform. Fractions 1-28 ml. each) gave no ma-.

terial. Fractions 29-30 (100 ml. each) gave 1.121 g. which wascrystallized from methylene chloride ether to give 0.62 g. of3-(2-pyridyl)-9H-dibenzo[c,f]-s-triazolo[4,3-d] azepine of melting point264266 C., raised to 266- 267.5 C. on recrystallization.

Anal.

Calcd. for C H N /zH O: C, 75.22; H, 4.73; N,

17.55. Found: C, 75.04; H, 4.43; N, 17.46.

Example 44 .-3[ Chloro)methyl-9H-dibenzo[c,f] -striazolo [4,3-a] azepineTo a stirred ice-cold solution of 6-hydrazinomorphanthridine (2.23 g.,0.01 mole) in dry tetrahydrofuran (25 ml.), under nitrogen was slowlyadded chloroacetyl chloride 1.12 g., 0.01 mole) in tetrahydrofuran (5ml.). After 15 minutes the ice-bath was removed and the reaction allowedto rise to ambient temperature (21-24 C.) and stirred for 1 hour. Thehydrochloric acid salt of the adduct was collected by filtration, washedwith ether and dried in a vacuum oven (40 C.) to give 3.32 g. ofproduct. This hydrochloric acid salt was combined with glacial aceticacid (40 ml.) and heated, under nitrogen in an oil bath at C. for 20minutes. The acetic acid was removed in vacuo and the residue mixed withwater, neutralized With sodium bicarbonate and extracted withchloroform. The extract was washed with Water, dried over anhydroussodium sulfate and concentrated. The residue was chromatographed onsilica gel (280 g.) with 5 percent methanol-95 percent chloroform. Theproduct thus obtained was crystallized from ethyl acetate Skellysolve Bhexanes to give 1.82 (65%) of 3[(chloro)methyl]-9H-dibenzo[c,f] striazolo[4,3-a]azepine of melting point 148150 C.

Anal.

Calcd. for C H N Cl: C, 68.20; H, 4.30; N, 14.91;

Cl, 12.59. Found: C, 66.94; H, 4.25; N, 15.44; Cl, 13.64.

Example 45 .3-[ (Dimethylamino methyl] -9H-dibenzo- [c,f] -s-triazolo[4,3-a] aziepine 19 amine (125 ml. of a saturated methanol solution(under nitrogen. The mixture was stirred at ambient temperature for oneand one-half hours, diluted with cold water and extracted withchloroform. The extract was washed with water, dried over anhydroussodium sulfate and concen- Anal.

Calcd. for C H N.,: C, 74.45; H, 6.25; N, 19.30. Found: C, 74.23; H,6.22; N, 19.61.

Example 46.-9H-Dibenzo[c,f]-s-triazolo[4,3-a1azepine To a stirredice-cold solution of 6-hydrazinomorphanthridine (13.40 g., 0.06 mole) indry chloroform (480 ml.) was added triethylorthoformate (44.4 g., 0.3mole), under nitrogen, and sulfuric acid (6.6 ml.) dropwise. After 15min. the ice-bath was removed and the reaction mixture allowed to riseto ambient temperature and then stirred for 2 hours. The chloroform waswashed with aqueous sodium bicarbonate solution, thereupon with water,dried over anhydrous sodium sulfate, treated with water and concentratedin vacuo. The oil was dissolved in ethyl acetate and crystallized togive 6.41 g. of melting point 154-160 C. and 5.05 g. of melting point165-l68 C. of 9H-dibenzo [c,f] s triazolo[4,3-a]azepine (overall yield82%). The analytical sample had a melting point 165-168 C.

Anal.

Calcd. for C15H11N3Z C, H, 4.75; N, 18.02. Found: C, 76.85; H, 4.76; N,17.50.

A mixture of 6(5H)-morphanthridinethione (2.25 g.; 0.01 mole) andnicotinic acid hydrazide (13.7 g.; 0.1 mole) was kept in a preheated oilbath at 215-225 C. for 1.75 hours. The mixture was then taken up inmethylene chloride and water and the resulting suspension was filteredto give Filtrate A and 2.7 g. of solid which solid was discarded.

Filtrate A was separated into layers, the organic layer was washed withsaturated salt solution, dried over anhydrous magnesium sulfate andevaporated. Crystallization from methanol gave 1.7 g. of3-(3-pyridyl)-9H-dibenzo[c,g]-s-triazolo[4,3-a]azepine of melting point266 267 C., unchanged on recrystallization.

Anal.

Calcd. for C H N C, 77.40; H, 4.55; N, 18.04. Found: C, 77.22; H, 4.67;N, 18.13.

Example 4 8.--3- 4-Pyridyl) -9H-dibenzo [c,f -s-triazolo- [4,3-a]azepine A mixture of 6(5H)-morphanthridinethione (2.25 g.; 0.01 mole)and isonicotinic acid hydrazide (13.7 g.; 0.1 mole) was kept in apreheated oil bath at 215-225 C. for 1.5 hours. The mixture was taken upin methylene chloride and water, the resulting suspension was filteredgiving filtrate A and a gummy solid which was discarded.

Filtrate A was separated into layers, the organic layer was washed withsaturated salt solution, dried over anhydrous magnesium sulfate andevaporated. Crystallization from methanol gave 1.2 g. of3-(4-pyridyl)-9H-dibenzo- [c,f]-s-triazolo[4,3-a]azepine of meltingpoint 271-273 C., raised to 273274.5 C. on recrystallization.

Anal.

Calcd. for C H N C, 77.40; H, 4.45; N, 18.05. Found: C, 77.27; H, 4.59;N, 17.81.

20 Example 49.-3- (Diethylamino methyl] -9H-dibenzo- [c,f]-s-triazolo[4.3-a] azepine To a stirred solution of 3 chloromethyl 9Hdibenzo- [c,f]-s-triazolo[4,3-a]azepine (2.82 g., 0.01 mole) in drytetrahydrofuran (100 ml.) was added sodium iodide (1.5 g., 0.01 mole)and diethylamine (10 ml.) under nitrogen. The mixture was stirred atambient temperature for 1% hours, mixed with cold water and extractedwith chloroform. The chloroform was washed with water, dried over sodiumsulfate and concentrated in vacuo. The residue was recrystallized twicefrom ethyl acetate-Skelly B to give 0.98 g., of melting point 132-135and 0.70 g., melting point 130-133 (overall yield 53%) of3-[(diethylamino) methyl]-9H-dibenzo [c,f] s triazolo [4,3-a]azepine.The analytical sample had a melting point of 132-134.

Anal.

Calcd. for C H N C, 75.44; H, 6.96; N, 17.60. Found: C, 74.97; H, 6.94;N, 17.95.

Example 5 0.3- Pyrrolidinomethyl -9H-dibenzo[c,f -striazolo [4,3-a]azepine To a stirred solution of 3-chloromethyl-9H-dibenzo-[c,f]-s-triazolo[4,3-a]azepine (2.82 g., 0.01 mole) in drytetrahydrofuran ml.) was added sodium iodide (1.50 g., 0.01 mole) andpyrrolidine 10 ml.) under nitrogen. The mixture was stirred at ambienttemperature for 1% hr., mixed with cold water and extracted withchloroform. The chloroform was washed with water, dried over sodiumsulfate and concentrated in vacuo. The residue was crystallized fromethyl acetate-Skelly B to give 1.315 g., (42% melting point 168-171 of3-(pyrrolidinomethyl)- 9H dibenzo[c,f] s triazolo[4,3-a]azepine. Theanalytical sampe had a melting point of 168-171.

Anal.

Calcd. for C H N C, 75.92; H, 6.37; N, 17.71. Found: C, 75.57; H, 6.45;N, 17.73.

Example 51.3- (2-Chloroethyl) -9H-dibenzo [c,f] -striazolo [4,3-a]azepine To a stirred ice-cold solution of 6-hydrazinomorphanthridine(2.23 g., 0.01 mole) in dry tetrahydrofuran (25 ml.) was slowly added3-chloropropionyl chloride (1.27 g., 0.01 mole) in tetrahydrofuran (5ml.) under nitrogen. After 20 minutes the ice bath was removed and themixture was allowed to rise to ambient temperature, and stirred for 1hr. The hydrochloric acid salt was collected by filtration, washed withether and dried in a vacuum oven (40) to give 3.50 g.

This hydrochloride was combined with glacial acetic acid (40 ml.) andheated under nitrogen in an oil bath at for 10-15 min. The acetic acidwas removed in vacuo and the residue mixed with water, neutralized withsodium bicarbonate and extracted with chloroform. The chloroform waswashed with water, dried over sodium sulfate and concentrated in vacuo.The residue was crystallized from methanol chloroform ethyl acetate togive 1.19 g., of melting point 178183 and 0.65 g., of melting point182-183 (overall yield 62%) of 3-(2-chloroethyl)- 9H-dibenzo [c,f]-s-triazolo[4,3-a]azepine The analytical sample had a melting point of182-183 Anal.

Calcd. for C H N Cl: C, 69.03; H, 4.77; N, 14.21;

Cl, 11.99. Found: C, 68.72; H, 4.77; N, 13.85; C1. 12.19.

Example 52.-3-[2-(Dimethy1amino) ethyl] -9H-dibenzo- [c,f] -s-triazolo[4,3-a] azepine To a stirred solution of 3-(2-chloroethyl)-9H-dibenzo-[c,f]-s-triazolo[4,3-a]azepine (1.48 g., 0.005 mole) in drydimethylformamide (2 5 ml.) was added potassium iodide (1.66 g., 0.01mole) and dimethylamine (15 ml. of a saturated solution in methanol)under nitrogen. The mixture was stirred at ambient temperature for 4hr., mixed with cold water and extracted with methylene chloride. Themethylene chloride extract was washed with water, dried over sodiumsulfate and concentrated in vacuo. The residue was crystallized fromethyl acetate Skellysolve B hexanes to give 0.96 g. (63%), of meltingpoint 110111. This was recrystallized from ethyl acetate-Skellysolve Bhexanes and seeded with the higher melting polymorph (melting point137-138") to give 0.90 g., of melting point 136l39 of3-[2-(dimethylamino)ethyl] 9H dibenzo[c,f] s triazolo [4,3-a]azepine.The analytical sample had a melting point of 135- 137.

Anal.

Calcd. for C H N C, 74.97; H, 6.62; N, 18.41. Found: C, 74.80; H, 6.81;N, 18.29.

Example 53.3-(2-Pyrrolidinoethyl)-9H-dibenzo- [c,f] -s-triazolo [4,3-a]azepine To a stirred solution of 3-(2-chloroethyl)-9H-dibenzo-[c,f]-s-triazolo[4,3-a]azepine (1.48 g., 0.005 mole) in drydimethylformamide (20 ml.) was added potassium iodide (1.66 g., 0.01mole) and pyrrolidine ml.) under nitrogen. The mixture was stirred atambient temperature for hr., mixed with water and extracted withchloroform. The chloroform was washed with water, dried over sodiumsulfate and concentrated in vacuo. The residue was crystallized fromethyl acetate Skelly B to give 1.11 g. (67%) of melting point 176-179"of 3-(2-py1rolidinoethyl) 9H dibenzo[c,f] s-triazolo- [4,3-a] azepine.The analytical sample had a melting point of 176179.

Anal.

Calcd. for C H N C, 76.33; H, 6.71; N, 16.96. Found: C, 76.01; H, 6.89;N, 17.34.

Example 5 4 .3-( 3-Chloropropyl) -9H-dibenzo- [c,f] -s-triazolo [4,3-a1azepine To a stirred ice-cold solution of6-hydrazinomorphanthriidine (6.69 g., 0.03 mole) in dry tetrahydrofuran(100 ml.) under nitrogen was slowly added 4-chlorobutyryl chloride (4.23g., 0.03 mole) in tetrahydrofuran (25 ml.). After minutes the ice-bathwas removed and the reaction allowed to rise to ambient temperature andstirred for 1 hr. The hydrochloride salt of the adduct was collected byfiltration, washed with ether and dried in a vacuum oven to give 10.37g.

This hydrochloride was combined with glacial acetic acid ml.) andheated, under nitrogen in an oil bath at 120 for 15 min. The acetic acidwas removed in vacuo and the residue mixed with water, neutralized withsodium bicarbonate and extracted with chloroform. The chloroform waswashed with water, dried over sodium sulfate and concentrated in vacuo.The oil was dissolved in ethyl acetate and crystallized uponconcentration to give 7.46 g., of melting point 179-181 and 0.56 g., ofmelting point ISO-181 (overall yield 89%) of 3-(3-chl0-ropropyl)-9H-dibenzo [c,f] -s-triazolo[4,3a] azepine. The analyticalsample was recrystallized from methanol-ethyl acetate and had a meltingpoint of 188-190 C.

Anal.

Calcd. for C H N Cl: C, 69.78; H, 5.21; N, 13.56;

Cl, 11.45. Found: C, 69.77; H, 5.20; N, 13.59; Cl, 11.98.

Example 55.3- 3-Dimethylamino propyl] -9H-dibenzo-[c,f]-s-triazolo[4,3-a]azepine dihydrochloride To a stirred solution of3-(3-chloropropyl)-9Hdibenzo[c,f]-s-triazolo[4,3-a]azepine (3.10 g.,0.01 mole) in dry dimethylformamide (50 ml.) was added sodium iodide(0.50 g.) and dimethylamine (10 ml.) of 25% aqueous solution) undernitrogen. The mixture was stirred and heated in a steambath overnight,mixed with water, neutralized with sodium bicarbonate and extracted withchloroform. The chloroform was dissolved in ethyl acetate, acidifiedwith ethanolic hydrogen chloride and 22 the salt recrystallized frommethanol ethyl acetate to give 0.245 g. of melting point 259-267" and1.105 g., of melting point 259- 266 (overall yield 69% of3-[3-dimethylamino)propyl] 9H dibenzo[c,f]-s-triaZolo[4,3-a]azepinedihydrochloride. The analytical sample had a melting point of 259-266.

Anal.

Calcd. for C H N Cl C, 61.38; H, 6.18; N, 14.32;

Cl, 18.12. Found: C, 61.11; H, 6.20; N, 14.48; Cl, 1 8.12.

Example 5 6 .--3- 3-Diethylamino propyl] -9H-dibenzo- [c,f]-s-triazolo[4,3a]azepine dihydrochloride To a stirred solution of3-(3-ch1oropropyD-9H-dibenzo[c,f]-s-triazolo[4,3-a]azepine (1.55 g.,0.005 mole) in dry dimethylformamide (50 ml.) was added potassium iodide(1.66 g., 0.01 mole) and. diethylamine (15 ml.) under nitrogen. Themixture was stirred at ambient temperature for 18 hr. but was raised to50 for 24 hr. to complete the reaction. The mixture was mixed with waterand extracted with chloroform. The chloroform was washed with water,dried over sodium sulfate and concentrated in vacuo. The oil wasdissolved in ethyl acetate, treated with Darco acidified with methanolichydrogen chloride and recrystallized from methanol ethyl acetate to give1.43 g. (68%), of melting point 258-263 of 3-[3-(diethylamino)propyl] 9Hdibenzo[c,f] s-triazolo[4,3-a] azepine dihydrochloride. Theanalyticalsample had a melting point of 256-262".

Anal.

Calcd. for C H N Cl C, 63.00; H, 6.73; N, 13.36;

Cl, 16.91. Found: C, 62.77; H, 6.89; N, 13.30; Cl, 17.50.

Example 57.3-(Pyrrolidinopropyl)-9H-dibenzo[c,f]-

s-triazolo [4,3-a] azepine dihydrochloride To a stirred solution of3-(3-chloropropyl)-9H-dibenzo[c,f]-s-triazolo[4,3-a]azepine (1.55 g.,0.005 mole) in dry dimethylformamide (50 ml), was added potassium iodide(1.66 g., 0.01 mole) and pyrrolidine (15 ml.) under nitrogen. Themixture was stirred at ambient temperature for 18 hr., mixed with waterand extracted with chloroform. The chloroform was washed with water,dried over sodium sulfate and concentrated in vacuo. The oil wasdissolved in ethyl acetate, acidified with methanolic hydrogen chlorideand recrystallized from methanol-ethyl acetate to give 1.92 g. (92%), ofmelting point 265-270" of 3-(3-pyrrolidinopropyl)-9H-dibenzo-[c,f]-s-triazolo[4,3-a]azepine dihydrochloride. The analytical samplehad a melting point of 265-270.

Anal.

Calcd. for C H N Cl C, 63.30; H, 6.28; N, 13.42;

Cl, 16.99. Found: C, 62.89; H, 6.38; N, 13.45; Cl, 17.20.

Example 58.-3-Vinyl-9Hdibenzo[c,f]-s-triazolo [4,3-a1azepine To astirred solution of 3-(2-chloroethyl)-9H-dibenzo[c,f]-s-triazolo[4,3-a]azepine (1.48 g., 0.005 mole) in drydimethylformamide (25 ml.) was added potassium iodide (1.66 g., 0.01mole) and diethylamine 10 ml.) under nitrogen. The mixture was stirredat ambient temperature for 1 /2 hr., mixed with water and extracted withch1oroform. The chloroform was washed with water, dried over sodiumsulfate and concentrated in vacuo. The residue was dissolved in methanolchloroform ethyl acetate decolorized with Darco and crystallized frommethanol chloroform ethyl acetate Skelly B to give 0.455 g. (35% of 3'vinyl-9H-dibenzo[c,f]-s-triazolo[4,3-a]azepine, of melting point 186187(incomplete melt). The analytical sample had a melting point of 186-187(incomplete melt).

3-hydroxymethyl-dibenzo [b,f] -s-triazolo [4,3-d] [1,4]

oxazepine;

3-hydroxymethyl-7-chloro-dibenzo [b,f -s-triazolo [4,3-d]

[1,4] oxazepine;

10-iodo-3- 3- (dipropylamino propyl] -dibenzo ['b,f, -s-

triazolo [4,3-d] 1,4]oxazepine;

8-amino-12-fiuoro-3 brorno) dibenzo [b,f -s-triazolo [4,3-d]1,4]oxazepine;

12-chloro-3 (propyl) dibenzo [b,f] -s-triazolo [4, 3-d] [1,4]

oxazepine;

7,1l-difluoro-3-(3-morpholinopropyl)dibenzo[b,f]-striazolo [4,3-d] [1,4]oxazepine;

11-propyl3- [2- (4-ethylpiperazino ethyl dibenzo b,f, -s-

triazolo[4,3-d] [1,4]oxazepine;

8,12-dimethoXy-3-(3-piperidinopropyl) dibenzo[b,f]-striazolo[4,3-d][1,4] oxazepine;

7-fluoro-12-propy1-3-(chloromethyl) dibenzo [b,f]-striazolo [4,3-d][1,4] oxazepine;

13 -rnethy1thio-3- chloromethyl dibenzo [b,f] -s-triazolo [4,3-d]1,4]oxazepine;

5-dimethylamino-3 (isopropyl) dibenzo [b,f] -s-triazolo [4,3-d][1,4]oxazepine;

8, 1 2-bis (ethylsulfonyl -3- (methyl dibenzo [b,f] -s-triazolo [4,3-d][1,410Xazepine;

or N-oxides of these compounds of formula II or III Which can be usedlike the free base compounds of formula II or III. Salt formation isachieved in conventional manner by reacting the compounds of formula IIor III with excess of a selected acid in a suitable medium e.g. water, alower alkanol, ether, or acetone and recovering the salt by evaporatingthe solvent, preferably in vacuo. The N-oxides are prepared by reactingthe compounds of formula II or III with an excess of a peracid such asperbenzoic acid, perphthalic acid, or m-chloroperbenzoic acid, in asolvent such as a lower alkanol, chloroform, or methylene chloride andrecovering the N-oxide by evaporating the solvent in vacuo.

We claim: 1. 3 (2 pyridyl)-9H-dibenzo[c,f]-s-triazolo[4,3-a] azepine.

2. 3 (3 pyridyl)-9H-dibenzo[c,f]-s-triazolo[4,3-a] azepine.

azepine.

References Cited UNITED STATES PATENTS 3,711,489 1/1973 Lombardino260296 P ALAN L. ROTMAN, Primary Examiner US. Cl. X.R.

260-294.8 A, 294.9, 295 A, 295.5 P, 247.1, 247.5 R, 268 PC, 293.59, 308R, 239 T, 247.2 A; 424248, 250, 263, 266, 267, 269

Column 5, lines 50-55, "C-=-C-C-N 'trizolo" should read triazolo UNITEDSTATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. Dated November26, 1974 Inv n Jackson B Hester, Jr. and Jacob Szmuszkovicz It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

should read C CC-N H R7 H R8 Column 10, l ine 50, "[1-4] should read[1,4] l ine 70,

Column 11, line 59, "chlorodizenbo" should read chlorodibenzo Col umn12, l ine 51, "[4,5-d]diazepine" should read [4,3-d][1,4]diazep| ne line 54, "9H di benzo" should read 9H-dibenzo Col umn 15, l i ne 45, "amino) should read ami noethyl l i ne 55, 9H- dibenzo-triazolo" should read9H-dlbenzo[b,f] s-tr|azolo l'i ne 56, "[4,5-d]diazepine" should read[4,5-d][l,4]d|azep| ne Column 14 l i ne. 73, "9-H-" should read -9H-Column 15, 1 ine 40, 'N, 22.0" should read N, 22.06 Col umn 16, l l ne15 "[1,4-" should read [1,4] Column 17, l ine 22, [4%] should read4,3'-d] l ine 56, "(dimethylaml nop ropyl should read (dimethylami no)propyl] l i ne 68, 'triazol u should read triazolo Column 19, line 1,"solution (under should read sol utl on) under Column 21, l i ne 64,"[5-D| should read [5- (Di l i ne 70, (10 ml of should read (10 ml ofColumn 22, l ine 5, "69% of" should read 69%) of l i ne 3, "B-[B-dishould read 3-[5- (Cll l ine 12, "3-[-Di" should read B-[B-(Di l ine 56,"B-(Pyrrol should read 5" (5-,Pyrrol Column 24, l me 15, "-2-[2-" shouldread -3-[2 Col umn 25, l ine 19,

"-3-ch1oro" should read -3-(chloro Signed and Sealed this Seventh D fSeptember 1976 [SEAL] Arrest.

RUTH C. MASON Arresting Officer C. MARSHALL DANN nmmisxiuner oj'latentsand Trademarks

1. 3-(2-PYRIDYL)-9H-DIBENZO(C,F)-S-TRIAZOLO(4,3-A) AZEPINE.